To understand normal development and differentiation, it is necessary to determine the mechanisms by which cells initiate new programs of gene expression and promote formation of specific cell lineages. Typically, this involves activation of genes that are transcriptionally silent and that may be incorporated into repressive chromatin structure. Evidence supports the idea that differentiation specific transcriptional regulators and enzymes that remodel chromatin structure cooperate to render genomic DNA more accessible to the transcriptional machinery. SWI/SNF enzymes alter nucleosome structure in an ATP dependent manner and facilitate transcription factor function in vitro and in vivo. Components of these enzymes are essential for embryonic development and some act as tumor suppressors. Additionally, SWI/SNF enzymes interact with other known tumor suppressors and are implicated in cell cycle control. Thus these enzymes are broadly required for normal cell function and their misregulation is implicated in tumor formation.We recently demonstrated a requirement for SWI/SNF enzymes in the initiation of skeletal muscle and adipocyte differentiation. Skeletal muscle differentiation has long been a model for studying fundamental principles of differentiation. Understanding skeletal muscle differentiation at a molecular level will have significant implications for investigating muscle regeneration and the formation of rhabdomyosarcomas, which are tumors of myogenic derivation. Adipocytes are a central component of the energy balance system in mammals. They store triglycerides during periods of nutritional abundance and release free fatty acids during periods of caloric deficiency. In humans, excessive development of adipocyte tissue, or obesity, affects 30 percent of the adults in the U.S. This population is at significantly increased risk for non-insulin dependent diabetes, coronary artery disease, and hypertension. Characterization of the molecular events that initiate and regulate adipocyte differentiation is therefore also an important medical concern. The goals of Aims 1 and 2 are to understand the mechanisms by which SWI/SNF chromatin remodeling enzymes promote development and differentiation, with emphasis on how SWI/SNF enzymes and key transcriptional regulators initiate new programs of gene expression.
Aim 3 will probe the generality of the requirement for SWI/SNF enzymes in different differentiation pathways and embryogenesis.
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